There has been much interest in the past few years regarding the role of nitric oxide (NO) in a variety of physiological phenomenon, particularly in the control of blood flow, vasodilation, etc. Recently, a number of compounds (NONOate and S-nitroso agents) have been synthesized and used to deliver nitric oxide to biological media. We have shown that the NONOate complexes sensitize hypoxic cells to ionizing radiation using in vitro model systems. In vivo NO administered to animals has revealed two exciting findings: l) NO provides protection against whole body irradiation, and 2) NO enhances radiation-induced tumor regrowth delay. These data provide evidence that NO delivered by NONOate complexes can sensitize tumor while providing protection to bone marrow and thus they may have utility in the treatment of human tumors with ionizing radiation. Preliminary studies using a murine tumor model have shown that the combination of melphalan and NO offers significantly more tumor control than melphalan alone. The combination of NO and other chemotherapy drugs are being evaluated. Since NO has been shown to be a key molecule in vasodilation it may be important in opening blood flow to hypoxic regions in tumors and reducing interstitial fluid pressure in tumors. Studies are underway to evaluate the NONOate NO delivery system in animal tumor models. It has been also demonstrated that NO provides protection against other forms of oxidative stress including hydrogen peroxide and organic hydroperoxides. These findings have implications for the use of NO delivery complexes in ischemia reperfusion injury situations.